1. Field of the Invention
Discussed herein are systems and methods for the inhibition of bromodomain and extra-terminal domain (BET) proteins to block induction of DUX4 mRNA and protein expression activity and assist in treatment of facioscapulohumeral muscular dystrophy (FSHD).
2. Description of the Related Art
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common type of muscular dystrophy (akin in prevalence to Duchenne muscular dystrophy and myotonic dystrophy) affecting approximately 12 in 100,000. It is a genetic muscle disorder that initially affects the muscles of the face, shoulder blades and upper arms. However, muscle degeneration is progressive and spreads to other muscles including those in the legs and hips. The disorder is most commonly detected due to muscle weakness in the shoulder blades resulting in muscles that no longer serve to correctly support the shoulder blades as a fulcrum for the arm. Thus, the shoulder blades often have excessive movement which can result in difficulty throwing or raising the arms above the head. Weakness of facial muscles resulting in difficulty puckering (and related activities such as drinking through a straw or whistling) are also common.
FSHD usually begins prior to age 20 and the disorder is progressive with muscle degeneration continuing throughout life. Sometimes FSHD is divided between adult-onset and infantile-onset forms with the adult onset (which includes onset in adolescence) being more common. Because it is characterized by progressive muscle weakness, in some individuals muscle weakness will eventually spread to the lower extremities, often resulting in affected individuals becoming wheelchair-bound. Further, pain and fatigue are frequent complaints and are presumably associated with muscle degeneration.
FSHD is almost always associated with a genetic flaw (mutation) that leads to a shorter than usual segment of DNA on chromosome 4. Specifically, FSHD type 1 (FSHD1) accounts for 95% of FSHD cases and is associated with contraction of the number of D4Z4 repeat units in the macrosatellite array at 4q35. FSHD2 (˜5% of cases) occurs in the absence of D4Z4 contraction and is believed caused by haplo-insufficiency or mutation of the SMCHD1 gene. Symptoms and effects of both types are generally the same.
The polymorphic D4Z4 array varies between 11 and >100 copies in healthy individuals, while FSHD1 patients retain 1-10 repeat units. Each repeat unit contains a copy of the DUX4 retrogene. While the disorder is believed to be genetically passed on, it also may occur spontaneously in certain cases.
There is currently no treatment available for FSHD and no clinical trials of promising treatments are ongoing. Nonsteroidal anti-inflammatories, or NSAIDs, are sometimes prescribed to provide comfort and mobility, but they have no effect on the underlying disease. Similarly, orthoses are often used to help support parts of the body where muscle degeneration is resulting in insufficient support, and certain types of surgery such as thoracoscapular fusion, where the shoulder blade is fused to the ribs to provide for more rigid support for the arms, are used in similar fashion. While these options can often increase mobility and function, they also have no effect on the underlying degeneration and therefore serve only to provide for comfort, as opposed to cure.
Despite recent advances in our understanding of the epigenetic mechanism of FSHD pathology, little insight has been gained into specific therapeutic targets amenable to small molecule drug intervention. Drug intervention can be beneficial for disorders such as FSHD as it can be significantly less invasive than surgery and, should it be able to target an underlying cause of the degeneration, can potentially further slow, halt, or possibly reverse the degeneration itself. Druggable targets that regulate DUX4 expression and evaluation of the therapeutic potential of the corresponding inhibitory compounds are desirable.